Alpha-[3-(1, 2, 3, 4-tetrahydroisoquinolyl)]-benzhydrol and salts thereof



United States Patent 2,989,532 a-[3-(1,2,3,4-TE1RAHYDROISOQU1NOLYL)]-BENZHYDROL AND SALTS THEREOF Leslie G. Humber and Stanley 0. Winthrop,Montreal,

Quebec, Canada, assign'ors to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware No Drawing. Filed June 19, 1959,Ser. No. 821,368 3 Claims. (Cl. 260-289) his invention relates to a newchemical compound, oc-[3-( 1,2,3,4-tetrahydroisoquinolyl) 1 -benzhydrol,and to hydrohalide salts thereof. It is also concerned with a process bywhich these compounds may be prepared.

Our new chemical compounds,a-[3-(l,2,3,4-tetrahydroisoquinolyl)]-benzhydrol and its hydrohalidesalts, particularly the hydrochloride salt, are useful as centralnervous system stimulants.

The compound, a-[3-(1,2,3,4-tetrahydroisoquinolyl) benzhydrol, may bereadily prepared by reacting 3-carbethoxy-l,2,3,4tetrahydroisoquinolinewith a Grignard reagent such as phenyl magnesium bromide. Moreparticularly, we prefer to react the hydrochloride salt of 3- carbethoxy1,2,3,4 tetrahydroisoquinoline with phenyl magnesium bromide in anethereal solution.

The starting material, 3-carbethoxy-1,2,3,4-tetrahydroisoquinoline, andits hydrochloride salt, may be readily prepared by procedures which aredescribed in the chemical literature; see: Swan, Journal of the ChemicalSociety (London), 1946, page 617.

Ordinarily we first prepare 3-carbethoxy-1,2,3,4-tetrahydroisoquinolineby a procedure such as that described by Swan, and then convert it toits hydrochloride salt, before converting the latter to the desired newcompound, a-[3-(1,2,3,4-tetrahydroisoquinolyl)]-benzhydrol, by the useof the Grignard reagent.

These chemical changes may be diagrammatically indicated as follows:

0000:4115 COOCzHs \/NE NH.HOI 3-carbethoxy-1, 2,3,g- Hydrochloride saltof tetrahydroisoqumohne 3-carbethoxy-1,2,3,4-

tetrahydroisoquinoline a- [3-(1,2,3,4-tetrahydroisoqulnolyl)]-benzhydrolExample 4.7 grams (0.023 mole) of3-carbethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride was preparedfrom 3- carbethoxy-l,2,3,4-tetrahydroisoquinoline by treating the latterwith ethereal hydrogen chloride.

The resulting solid hydrochloride was then addedv slowly to an etherealsolution of 0.28 mole of phenyl magnesium bromide. The mixture wasrefluxed for 3 hours, and then allowed to stand at room temperature for15 hours.

A 20 percent solution of aqueous ammonium chloride was then added to thereaction mixture in order to decompose the intermediate reactionproduct. Benzene was then added and a benzene-ether extract secured.This extract was then removed, washed with water, and dried over sodiumsulfate. It was then evaporated to dryness in vacuo, i.e. at a pressureless than atmospheric, and there were thus obtained 6.6 grams ofu-[3-(1,2,3,4- tetrahydroisoquinolyl) ]-benzhydrol.

The product was twice crystallized from ethanol solution and, afterpurification, it had a melting point of 169l70 C. Analysis confirmed theempiric formula C22H21NO.

Calculated: C, 83.80; H, 6.71. 6.89.

An ethanolic solution of hydrogen chloride was then added to a smallamount of the a-[3-(l,2,3,4-tetrahydroisoqninolyl)]-benzhydro1 productand there was thus obtained oz [3 (l1,2,3,4 tetrahydroisoquinolyD]benzhydrol hydrochloride. This salt crystallized from absolute ethanolas colorless crystals having a melting point in excess of 250 C.Analysis confirmed the empiric formula Calculated: N, 3.98; CI, 10.08.10.02.

Other hydrohalide salts may be prepared in a similar manner.

We claim:

1. A compound selected from the group which consists ofa-[3-(1,2,3,4-tetrahydroisoquinolyl)]-benzhydro1 and its hydrohalidesalts.

2. a- [3-( 1,2,3,4-tetrahydroisoquinolyl) -benzhydrol.

3. w- [3-( 1,2,3,4-tetrahydroisoquino1yl) -benzhydrol hydrochloride.

Found: C, 83.80; H,

Found: N, 3.95; CI,

References Cited in the file of this patent Remfry et al.: BerichteDeutsche Chemische Gessellschaft, vol. 41, pp. 1007-9 (1908).

Dyson et al.: Journal Chemical Society (London) (1937), page 1724.

Ashworth et al.: Journal Chemical Society (London), pages 809 812 1939).

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OFA-(3-(1,2,3,4-TETRAHYDROISOQUINOLYL))-BENZHYDROL AND ITS HYDROHALIDESALTS.